title: Sequestration of AS-DACA into acidic compartments of the membrane trafficking system as a mechanism of drug resistance in rhabdomyosarcoma.
abstract: The accumulation of weakly basic drugs into acidic organelles has recently been described as a contributor to resistance in childhood cancer rhabdomyosarcoma (RMS) cell lines with differential sensitivity to a novel topoisomerase II inhibitor, AS-DACA. The current study aims to explore the contribution of the endocytic pathway to AS-DACA sequestration in RMS cell lines. A 24-fold differential in AS-DACA cytotoxicity was detected between the RMS lines RD and Rh30. The effect of inhibitors of the endocytic pathway on AS-DACA sensitivity in RMS cell lines, coupled with the variations of endosomal marker expression, indicated the late endosomal/lysosomal compartment was implicated by confounding lines of evidence. Higher expression levels of Lysosomal-Associated Membrane Protein-1 (LAMP1) in the resistant RMS cell line, RD, provided correlations between the increased amount and activity of these compartments to AS-DACA resistance. The late endosomal inhibitor 3-methyladenine increased AS-DACA sensitivity solely in RD leading to the reduction of AS-DACA in membrane trafficking organelles. Acidification inhibitors did not produce an increase in AS-DACA sensitivity nor reduce its sequestration, indicating that the pH partitioning of weakly basic drugs into acidic compartments does not likely contribute to the AS-DACA sequestering resistance mechanism evident in RMS cells.
authors.affiliation: The Tumour Bank, Children's Cancer Research Unit, the Children's Hospital at Westmead, Westmead, NSW 2145, Australia. daniel.catchpoole@health.nsw.gov.au.
authors.forename: Marissa
authors.initials: M
authors.lastname: Williams
authors.forename: Daniel
authors.initials: D
authors.lastname: Catchpoole
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004351:Drug Resistance / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D011992:Endosomes; D006801:Humans; D021381:Protein Transport; D012208:Rhabdomyosarcoma
chemical_list: D000970:Antineoplastic Agents